2-hydroxy-3-methoxy-5-allyl benzamides

ABSTRACT

WHEREIN R is selected from the group consisting of hydrogen, alkyl of one to seven carbon atoms and acyl of an organic carboxylic acid of one to 18 carbon atoms, R1 and R2 are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of one to seven carbon atoms, aryl and cycloalkyl and when taken together with the nitrogen atom form a heterocyclic which may contain another heteroatom, which products possess outstanding choleretic properties far superior to dehydrocholic acid. The invention also relates to a novel process and novel intermediate for the preparation of the said benzamides of Formula I.   An amide of 2-hydroxy-3-methoxy-5-allyl-benzoic acid of the formula

United States Patent Clemence et al.

[54] 2-HYDROXY-3-METHOXY-5-ALLYL BENZAMIDES [72] Inventors: FrancoisClemence, Rosny-sous-Bois;

Odile Le Martret, Paris, both of France [73] Assignee:. Roussel Uclaf,Paris, France 22 Fileds Sept. 25, 1968 21 Appl.No.: 762,606

Related US. Application Data [63] Continuation-impart of Ser. No.743,576, June 6,

1968, abandoned.

[30] Foreign Application Priority Data June 6, 1967 France ..67l09297Sept. 6, i967 France ..67l00154 [52] US. Cl ..260/488, 260/247.2,260/247.7,

424/31 1 [5 l lnt. Cl. ..C07c 69/02 [58] Field of Search ..260/559 S,488 CD [56] References Cited UNITED STATES PATENTS 1,939,496 12/1933Guggenheim .260/559 [451 June6, 1972 3,262,946 7/1966 Moffett ..260/559X Primary Examiner--Alex Maze] Assistant Examiner-James l-l. TurnipseedAttorney-Hammond and Littell [57] ABSTRACT An amide of2-hydroxy-3-methoxy-5-allyl benzoic acid of the formula CON Hr-CH=GH3(I) wherein R is selected from the group consisting of hydrogen, alkylof one to seven carbon atoms and acyl of an organic carboxylic acid ofone to 18 carbon atoms, R, and R are selected from the group consistingof hydrogen, substituted and unsubstituted alkyl of one to seven carbonatoms, aryl and cycloalkyl and when taken together with the nitrogenatom form a heterocyclic which may contain another heteroatom, whichproducts possess outstanding choleretic properties far superior todehydrocholic acid. The invention also relates to a novel process andnovel intermediate for the preparation of the said benzamides of FormulaI.

14 Claims, N0 Drawings 1 Z-HYDROXY-Zi-METHOXY-5-ALLYL BENZAMIDES PRIORAPPLICATIONS The present application is a continuation-in-part applica-5 tion of our copending, commonly assigned application, Ser. No. 743,756filed June 6, 1968, now abandoned.

OBJECTS or THE INVENTION It is an object of the invention to provide thenovel benzamides of Formula I.

It is another object of the invention to provide novel intermediates forthe benzamides of Formula I. It is another object of the invention toprovide a novel process for the preparation of the benzamides.

It is an additional object of the invention to provide novel therapeuticcompositions having a high choleretic activity.

It is a further object of the invention to provide a novel method ofincreasing bile secretion in warm blooded animals.

These and otherobjects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The novel benzamides of the invention have the formula R1--C ON/ *EFEE=EEZ C 1 1 1.

wherein R is selected from the group consisting of hydrogen, alkyl ofone to seven carbon atoms and acyl of an organic carboxylic acid of oneto 18 carbon atoms, R and R are selected from the group consisting ofhydrogen, substituted and unsubstituted alkyl of one to seven carbonatoms, aryl. ad cycloalkyl and when taken together with the nitrogenatom form a heterocyclic which may contain another heteroatom, R and Rare the same or different and are preferably hydrogen, alkyl of one toseven carbon atoms which may be substituted with hydroxy or acyloxy of alower aliphatic carboxylic acid, cycloalkyl of five'to seven carbonatoms, monocyclic aryl and when taken together with the nitrogen atommay be a 5 to 7 membered heterocyclic radical which may contain anotherheteroatom.

Examples of suitable compounds of Formula I are2-hydroxy-3-methoxy-5-allyl-N-(B-hydroxyethyl)-benzamide;2,3-dimethoxy-5 allyl-N-(B-hydroxyethyl)-benzamide;2-hydroxy-3-methoxy-5-allyl-N-morpholinobenzamide;2-hydroxy-3-methoxy-5-allyl-N-piperidinobenzamide;2-hydroxy-3-methoxy-5-allyl-N-pyrrolidinobenzamide;2-hydroxy-3-methoxy-5-allyl-N-(B-hydroxypropyD-benzamide;2-hydroxy-3-methoxy-5-allylbenzanilide;2-hydroxy-3-methoxy-5-allyl-N-cyclohexylbenzamide;2-hydroxy-3-methoxy-5-allyl-N-n-propylbenzamide;2-acetoxy-3-methoxy-S-allylbenzanilide;2-acetoxy-3-methoxy-5-allyl-N-n-propylbenzamide;2-acetoxy-3-methoxy-5-allyl-N-cyclohexylbenzamide;2-hydroxy-3-methoxy-5-allyl-N-diethylbenzamide;2-hydroxy-3-methoity-S-allylbenzamide;2-hydroxy-3-methoxy-5-allyl-N-(a,a-dimethyl-B-hydroxyethyl)-benzamide2-acetoxy-3-methoxy-5-allyl-N-(B-acetoxyethyl)-benzamide.

The novel process of the invention for the preparation of 65 benzamidesof Formula I comprises condensing a nitrogen compound of the formulawherein R, and R, have the above definition with a carboxylic functionalderivative of 2-hydroxy-3-methoxy-5-allyl-benzoic acid to form thecorresponding benzamide which can be esterified or etherified in the2-position. The carboxylic acid functional derivative is preferablychosen from the group consisting of the acid halide such as chloride orbromide, the acid anhydride, a mixed acid anhydride and a lower alkylester. The mixed anhydride can be formed in situ from 2-hydroxy-3-methoxy-S-allyl-benzoic acid and a dialkylcabodiimide.

A variation of the process of the invention comprises reacting2-hydroxy-3-methoxy-S-allyl-benzoic acid with an esterifying agent of anorganic carboxylic acid of one to 18 carbon atoms to form thecorresponding 2-acyloxy-3-methoxy-5-allylbenzoic acid, converting thelatter into a carboxylic acid functional derivative by reaction with ahalogenating agent or a dehydrating agent, and reacting the latter witha nitrogen compound of Formula II to form the corresponding 2-acyloxy-3-methoxy-5-allyl-benzamide which may be saponified to form thecorresponding 2-hydroxy compound which can be etherified or esterifiedif desired.

Another variation of the process of the invention comprises reacting acarboxylic functional derivative of 2-hydroxy-3- methoxy-benzoic acidwith a nitrogen compound of Formula II to form the corresponding2-hydroxy-3-methoxy-benzamide, reacting the latter with an allyl halideto form the corresponding 2-allyloxy-3-methoxy-benzamide and subjectedthe latter to a Claisen transformation to form the corresponding2-hydroxy-3-methoxy-S-allyl-benzamide which can be esterified oretherified.

Examples of suitable organic acids of one to 18 carbon atoms may bederived from an aliphatic, aromatic, cycloaliphatic or heterocycliccarboxylic acid. Examples of suitable acids are alkanoic acids, such asformic acid, acetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid,,B-trimethyl propionic acid, heptanoic acid, caprylic acid, pelargonicacid, capric acid, undecylic acid, lauric acid, myristic acid, palmiticacid and stearic acid; alkenoic acids, such as undecylenic acid andoleic acid; cycloalkyl carboxylic acids, such as cyclopentyl carboxylicacid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid andcyclohexyl carboxylic acid; cycloalkyl alkanoic acids, such ascyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionicacid and cyclohexyl propionic acid; arylalkanoic acids, such as phenylacetic acid and phenyl propionic acid; aryl carboxylic acids, such asbenzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids, suchas phenoxy acetic acid, p-chlorphenoxy acetic acid, 2,4-dichlorophenoxyacetic acid, 4-ter-butylphenoxy acetic acid, 3-phenoxy propionic acidand 4-phenoxy butyric acid; heterocyclic carboxylic acids, such asfurane-Z-carboxylic acid, S-terbutylfurane-Z-carboxylic acid,S-bromo-furane-Z- carboxylic acid and nicotinic acids; B-ketoalkanoicacids, such as acetylacetic acid, propionylacetic acid and butyrylaceticacid; amino acids, such as diethylaminoacetic acid and aspartic acid.

The condensation of the nitrogen compound of Formula II with2-hydroxy-3-methoxy-5-allyl-benzoic acid derivative is preferablyeffected in the presence or absence of an inert organic solvent from C.to the reflux temperature of the specific nitrogen compound. Whencondensing the 2-acyloxy compound with the nitrogen compound of FormulaII, the functional derivative is preferably an acid halide and thereaction is effected in an inert solvent below 50 C. in the presence ofan acid acceptor.

Formation of the 2-allyloxy derivative is preferably effected with anally] halide in the presence of a alkali agent and the Claisentransposition is preferably effected at C to 250 C.

The etherification of the 2-hydroxy-3-methoxy-5-allylbenzamides ispreferably effected with an alkyl halide or sulfate in a organic medium.The esterification of the said benzamides is preferably effected with anorganic carboxylic acid halide in the presence of an alkali metahydroxide.

The novel choleretic compositions of the invention consist of aneffective amount of at least one benzamide of Formula I, and a majoramount of a pharmaceutical carrier. The said compositions may be in theform of injectable solutions or suspensions, tablets, coated tablets,cachets, capsules, aromatic powder, granules, emulsions andsuppositories prepared in the usual manner. Thy contain preferably from100 to 200 mg of the active compound.

The compositions are useful for the treatment of dyspeptic disturbancesdue to a biliary deficiency, hepatobiliary functional disturbances,alimentary intolerances, urticarias, pruritus, migraines andconstipation of hepatic origin.

The novel method of the invention for increasing bile secretion inwarm-blooded animals comprises administering to warm-blooded animals asafe and efiective amount of at least one benzamide of Formula I. Thesaid amides are administered orally, transcutaneously or rectally. Theusual useful daily dosage is 1 to 50 mg/kg depending upon the method ofadministration of the benzamide of Formula 1.

1n the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I PREPARATION of 2-hydroxy-3-methoxy-5-allyl-N-(,8-hydroxyethyl)-benzamide 36 g. of ethyl ester of2-hydroxy-3-methoxy-5-allyl-benzoic acid (obtained by the processdescribed by PEARL et al., J. Amer. Chem. Soc., Vol. 71, 1,067-1,068,1949) and 61 g of ethanolamine were admixed and left to stand for 1 hourat ambient temperature after which it was heated for 1 hour a 120 C. Themixture was extracted with chloroform and the organic phases were washedwith half diluted hydrochlorid acid, then with water, and the chloroformevaporated off. The residue, after recrystallization from benzene, was a78 percent yield of2-hydroxy-3-methoXy-5-allyl-N-(B-hydroxyethyl)-benzamide having amelting point of 95 C. The product appeared in the form of colorlesscrystals which were insoluble in water and soluble in dilute sodiumhydroxide.

Analysis: C, ,H,,NO,; molecular weight 251.27 Calculated: C% 62.12 11%6.82 N% 5.57

Found: 62.4 6.8 5.6

l. R. Spectrum Nujol:

H at 3500 cm NH at 3320 cm C O at 1650 cm CH CH at 905 and 985 cm U. V.spectrum ethanol: A max. at 316 and 218 my. Shoulder at 250 mp A min. at275 m As far as is known, this compound is not described in theliterature.

EXAMPLE II Analysis: C l-I, ,NO,; molecular weight 21 1.21 Calculated:N% 6.64 Found: 6.69

As far as is known, this compound is not described in the literature.

Step B: Preparation of 2-hydroxy-3- -methoxy-5-allyl-N-(fl-hydroxyethyD-benzamide 12 g. of2-hydroxy-3-methoxy-N-(,B'hydroxy-ethyl)-benzamide, 7.6 g of allylbromide, 7.87 g of potassium carbonate in 12 cc of acetone, were admixedand heated at reflux for 8 hours. After the addition of 50 cc of water,the mixture was extracted with chloroform and the organic phases werewashed with IN sodium hydroxide and distilled in vacuo. The crude2-allyloxy-3-methoxy-N-(B-hydroxyethyl)-benzamide thus obtained washeated gradually to 200 C. and maintained at reflux for 30 minutes.Dilute sodium hydroxide was added thereto and the mixture was extractedwith chloroform. The alkaline phase was acidified with dilutehydrochloric acid and extracted with chloroform. After evaporation ofthe solvent, the residue was crystallized from ether to obtain2-hydroxy-3- methoxy-S-allyl-N-(B-hydroxyethyl)-benzamide with a meltingpoint of C.

As far as is known, 2-allyloxy-3-methoxy-N-(/3-hydroxyethyl)-benzamideis not described in the literature.

EXAMPLE Ill Preparation of 2,3-dimethoxy-5-allyl-N-(B-hydroxyethyl)-benzamide 20 g. of 2-hydroxy-3-methoxy-5-allyl-N-(B-hydroxyethyl)-benzamide (obtained in Example I) were dissolved in cc ofN sodiumhydroxide and after heating to 40 C., 20.05 g. of methyl sulphate wereadded thereto while maintaining an alkaline pH by adding N sodiumhydroxide. The mixture stood for one hour, then was filtered and theprecipitate was recrystallized from ethyl acetate to obtain2,3-dimethoxy-5- allyl-N-(B-hydroxyethyl)-benzamide in a yield of 60percent and having a melting point of 74 C.

The product appeared in the form of colorless crystals which wereinsoluble in water and dilute sodium hydroxide.

Analysis: C H NO molecular weight 265.29 Calculated: N% 5.28

Found: 5.36

l. R. Spectrum Nujol Absence of OH As far as is known, this compound isnot described in the literature.

EXAMPLE IV Preparation of 2-hydroxy-3-methoxy-5-al1yl-N-(B-hydroxypropyl)-benzamide A mixture of 10.5 g. of isopropanolamineand 5 g. of the ethyl ester of 2-hydroxy-3-methoxy-benzoic acid wereheated at C. for 1 hour and the solution thus obtained was extractedwith chloroform. The organic phases were washed with 6N hydrochloricacid, then with water and evaporated to dryness to obtain a yield of 55percent of 2-hydroxy-3- methoxy-S-allyl-N(,8-hydroxypropyl)-benzamidehaving a melting point of 86 C.

The product appeared in the form of colorless crystals soluble in dilutesodium hydroxide and insoluble in water.

Analysis: C,.,H ,NO,; molecular weight 265.29 Calculated: N% 5.28 Found:5.36

As far as is known, this compound is not described in the literature.

EXAMPLE V Preparation of 2-hydroxy-3-methoxy-5-allyl-N-morpholin0-benzamide 25 g. of the ethyl ester of 2-hydroxy-3-methoxy-5-allylbenzoicacid and 61 g. of morpholine were heated at reflux for 4 hours and thenthe excess morpholine was distilled ofi under The product appeared inthe form of colorless crystals insoluble in water and soluble in dilutesodium hydroxide.

Analysis: C I-1, 140 molecular weight 277.30 Calculated: N% 5.05 Found:5.10

As far as is known this compound is not described in the literature.

EXAMPLE Vl Preparation of2-hydroxy-3-methoxy-5-allyl-N-piperidinobenzamide A mixture of 25 g. ofthe ethyl ester of 2-hydroxy-3-methoxy-5-allylbenzoic acid and 60 g. ofpiperidine were heated at reflux for 3 hours and then the excesspiperidine was distilled off under reduced pressure. The residue wasextracted with chloroform and the organic phases were washed with dilutehydrochloric acid, then with water and evaporated to dryness. Theresulting residue was recrystallized from isopropyl ether to obtain a65.5 percent yield of 2-hydroxy-3-methoxy-5-allyl- N-piperidinobenzamidehaving a melting point of 90 C. and occurring in the form of colorlesscrystals.

Analysis: C H NO molecular weight 275.33 Calculated: N% 5.08 Found: 5.15

As far as is known, this compound is not described in the literature.

EXAMPLE Vll Preparation of2-hydroxy-3-methoxy-S-allyl-N-pyrrolidinobenzamide A mixture of 25 g. ofthe ethyl ester of 2 hydroxy-3-methoxy-5-allylbenzoic acid and 50 g. ofp yrrolidine were heated at reflux for 3 hours and after distilling offthe excess amine, the residue was extracted with chloroform. The organicphases were washed with dilute hydrochloric acid, then water andevaporated to dryness. The residue was crystallized from acetone toobtain 16.17 g (Yield 58.5 percent) of 2-hydroxy-B-methoxy-5-allyl-N-pyrrolidinobenzamide, in the form of colorlesscrystals, melting at 154 C.

Analysis: C l-1 190 molecular weight 261.31 Calculated: C% 68.94 H% 7.32N% 5.36 Found: 69.00 7.20 5.50

As far as is known, this compound is not described in the literature.

EXAMPLE Vlll Preparation of 2-hydroxy-3-methoxy-5-allylbenzanilide StepA: 2-acetoxy-3-methoxy-5-allylbenzoic acid 35 g. of2-hydroxy-3-methoxy-5-allylbenzoic acid, (Scheuch Liebigs Annalen derChemie Vol. 125, pg. 17), were suspended in 32 cc of acetic anhydrideand after the addition of a few drops of sulphuric acid, the mixture washeated at 50-60 for 15 minutes. After cooling, 33 cc of water were addedto the mixture which was allowed to stand for 2 hours before extractingwith ether. The ether extracted was evaporated to dryness and theresidue crystallized from benzene to obtain a yield of 74.5 percent of2-acetoxy-3- methoxy-S-allyl-benzoic acid in the'form of colorlesscrystals melting at 127 C.

Analysis: C I-1 molecular weight 250.26 Test with iron perchloride:negative (absence of phenol) As far as is known, this compound is notdescribed in the literature.

Step B: 2-acetoxy-3-methoxy-S-allylbenzoic acid chloride:

10 g. of 2-acetoxy-S-methoxy-S-allyl-benzoic acid were dissolved in 40cc of thionyl chloride and heated at reflux until the end of gasevolution. The excess thionyl chloride was eliminated and the residuedistilled at reduced pressure produced an oil boiling at l60161 C. under2 mm of mercury which slowly crystallized to obtain a yield of 62percent of 2-acetoxy-3-methoxy-S-allylbenzoic acid chloride melting at50 C.

Analysis: C l-I CIO molecular weight 268.57 Calculated: Cl% 13.19 Found:13.22

As far as is known, this compound is not described in the literature.

Step C: 2-acetoxy-3-methoxy-5-allylbenzanilide A mixture of 2.63 g. oftriethylamine and 2.15 g of aniline in 25 cc of acetone were added to asolution of 6.37 g. of 2- acetoxy-3-methoxy-5-allylbenzoic acid chloridein 25 cc of acetone while maintaining the temperature between +l0 and+15 C. The resulting mixture was stirred at ambient temperature for 2 /2hours and then was filtered. After evaporating off the acetone, theresidue was crystallized from alcohol to obtain a yield of 60 percent of2-acetoxy-3-methoxy-5-allylbenzanilide.

The product appeared in the form of colorless crystals, in-

soluble in water and dilute sodium hydroxide.

Analysis: C H NO molecular weight 325.19 Calculated: N% 4.30

Found: 4.34-4.32

As far as is known, this compound is not described in the literature.

Step C: 2-hydroxy-3-methoxy-5-allylbenzanilide 1.62 g of2-acetoxy-3-methoxy-5-allylbenzanilide were dissolved in an excess of0.4 N methanolic potassium hydroxide and after standing for 15 minutes,the pH was adjusted to 7 by adding N/l0 hydrochloric acid thereto. Themethanol was distilled off and the residue was dissolved in water andthe solution acidified to pH of l and extracted with chloroform. Theorganic phases were washed with water, evaporated to dryness and theresidue was crystallized from alcohol to obtain2-hydroxy-3-methoxy-5-allylbenzanilide melting at 140 C. and in the formof colorless crystals, in soluble in water and soluble in dilute sodiumhydroxide.

Analysis: C I-1 ,190 molecular weight 283.31 Calculated: N% 4.94 Found:5.04-5.02

As far as is known, this compound is not described in the literature.

EXAMPLE IX Preparation of 2-hydroxy-3-methoxy-5-allyl-N-npropylbenzamideStep A: 2-acetoxy-3-methoxy-5-ally1-N-n-propylbenzamide To a solution of3.6 g of 2-acetoxy-3-methoxy-5-a1lylbenzoic acid chloride, obtained inStep B of Example V111 and 1.1 g of triethylamine in 25 cc of acetone, asolution of 0.86 g of n-propylamine in 25 cc of acetone was slowlyaddedwhile maintaining the temperature between +10 and +15 C. Thesolution was filtered and the filtrate was evaporated to dryness underreduced pressure. The residue was crystallized from isopropyl ether toobtain a yield of 61 percent of 2-acetoxy-3-methoxy-S-allyl-N-n-propylbenzamide. The product appeared in the form ofcolorless crystals insoluble in dilute sodium hydroxide and melting atC.

Analysis: C l-l Nm; molecular weight 29 1.34 Calculated: N% 4.80 Found:4.80

As far as is known, this com ound is not described in the literature.

Step B: 2-hydroxy-3-methoxy-5-allyl-N-n-propylbenzamide l g of2-acetoxy-3-methoxy-5-allyl-N-n-propylbenzamide was dissolved in anexcess of 0.9 N methanolic potassium hydroxide and after standing for 30minutes, the pH was adjusted to 7 by adding dilute hydrochloric acidthereto. After evaporation of the methanol, the residue was dissolved inwater, and hydrochloric acid was added. The solution was extracted withchloroform and the organic phases were washed with water and distilledto dryness to obtain an amorphous product which upon re-crystallizationfrom isopropyl ether gave 0.51 g of2-hydroxy-3-methoxy-5-allyl-N-n-propylbenzamide (yield: 60 percent) inthe form of colorless crystals and melting at 95 C., insoluble in waterand soluble in dilute sodium hydroxide.

Analysis: molecular weight 249.29 Calculated: Found:

u io ni As far as is known this compound is not described in theliterature.

EXAMPLE X Preparation of2-hydroxy-3-methoxy-5-ally1-N-cyclohexylbenzamide Step A:2-acetoxy-3-methoxy-5-allyl-N-cyclohexylbenzamide Using the process ofStep A of Example IX, 5.57 g of 2- acetoxy-3-methoxy-5-allylbenzoic acidchloride, 2.25 g of cyclohexylamine, 2.29 g. of triethylamine and 50 ccof acetone give after recrystallization from isopropyl ether 3.03 g(yield: 44 percent) of 2-acetoxy-3-methoxy-5-allyl-N-cyclohexylbenzamide in the form of colorless crystals, insoluble inwater and dilute sodium hydroxide and melting at 100 C.

Analysis: C H NO molecular weight 331.40 Calculated: N% 4.22 Found: 4.45

As far as is known, this compound is not described in the literature.Step B: 2-hydroxy-3-methoxy-S-allyl-N-cyclohexylbenzamide Using theprocess of Step B of Example IX, 1 g. of2-acetoxy-3-methoxy-S-allyl-N-cyclohexylbenzamide gave aftercrystallization from isopropyl ether, 0.45 g. (51.5 percent yield) of2-hydroxy-3-methoxy-5-allyl-N-cyclohexylbenzamide in the form ofcolorless crystals insoluble in water and soluble in dilute sodiumhydroxide and melting at 132 C.

Analysis: C H NO molecular weight 289.35 Calculated: N% 4.84 Found: 4.84

As far as is known, this compound is not described in the literature.

EXAMPLE XI Preparation of 2-hydroxy-3-methoxy-5-allyl-N-diethylbenzamideStep A: 2-hydroxy-3-methoxy-N-diethylbenzamide 16.81 g of2-hydroxy-3-methoxybenzoic acid were dissolved in 400 cc of acetone and30.35 g of triethylamine and then 22 cc of ethyl chloroformate wereadded thereto. The solution was filtered to remove the triethylaminehydrochloride thus formed and 14.63 g of diethylamine were addedthereto, the solution stood for about 12 hours.

The acetone was distilled ofi and the residue was dissolved in Npotassium hydroxide in ethanol and after standing for about 12 hourscontact, the solution was filtered. The ethanolic solution was acidifiedwith N hydrochloric acid, and then evaporated under reduced pressure.The residue was dissolved in ether, washed with water and evaporated offto dryness to obtain a 43 percent yield of 2-hydroxy-3-methoxy-N-diethylbenzamide which occurred after crystallization from isopropylether, in the form of colorless crystals melting at 86 C.

Analysis: C,,H,,NO,; molecular weight 223.26 Calculated: N% 6.27 Found:6.30

As far as is known, this compound is not described in the literature.

Step B: 2-allyloxy-3-methoxy-N-diethylbenzamide A suspension of 9.6 g of2-hydroxy-3-methoxy-N-diethylbenzamide, 5.71 g of allyl bromide and 5.93g of potassium carbonate in 50 cc of acetone was refluxed for 8 hoursafter which the acetone was distilled off in vacuo. The residue wasdissolved in ether and washed with N sodium hydroxide and then water.After evaporating off the ether, a residual oil was distilled and thefraction (8 g.) boiling between 137 and 139 C. under a pressure of 0.3mm was collected which was 2-allyloxy-3-methoxy-N-diethylbenzamide.

Analysis: C H NO molecular weight 263.32 Calculated: N% 5.31 Found: 5.30

As far as is known, this compound is not described in the literature.

Step C: 2-hydroxy-3-methoxy-5-allyl-N-diethyl-benzamide 8 g of2-allyloxy-3-methoxy-N-diethylbenzamide produced in step B weregradually heated to 210 C. and maintained for half an hour at thistemperature. After cooling, the product was extracted with N sodiumhydroxide which was acidified with dilute hydrochloric acid andextracted with ether. The oil obtained after evaporating ofi' the etherwas distilled under low pressure to collect the fraction boiling betweenand C. under a pressure of 0.4 mm. This was a 25 percent yield of2-hydroxy-3-methoxy-5-allyl-N-diethyl-benzamide.

Analysis: C H NO molecular weight 263.32 Calculated: N% 5.31 Found: 5.26

As far as is known, this compound is not described in the literature.

EXAMPLE Xll Preparation of 2-hydroxy-3-methoxy-5-allyl-N-(a,a-dimethyl-B-hydroxycthyl)-benzamide 30 g of the ethyl ester of2-hydroxy-3-methoxy-5-allylbenzoic acid were slowly added to 74.8 g of2-amino-2- methyl-l-hydroxypropane and the mixture was heated for 1 hourat 130 C. After cooling, the mixture was extracted with chloroform andthe organic phase was washed with dilute hydrochloric acid, then withwater and the chlorofonn was evaporated off under low pressure to obtaincrystals which were recrystallized from isopropyl ether, to obtain a 57percent yield of 2-hydroxy-3-methoxy-5-allyl-N-(a,a-dimethyl-B-hydroxyethylbenzamide in the form of colorless crystals and melting at98 C. (yield: 57 percent).

Analysis: C H NQ; molecular weight 279.32 Calculated: N% 5.01 Found:5.03

As far as is known, this compound is not described in the literature.

EXAMPLE X111 Preparation of 2-acetoxy-3-methoxy-5-allyl-N-(B-acetoxyethyl)-benzamide A few drops of concentrated sulfuric acidwere added to 17.96 g of2-hydroxy-3-rnethoxy-5-allyl-N-(B-hydroxyethyl)- benzamide (prepared inExample I) in suspension in 22 cc of acetic anhydride, while maintainingthe temperature at about C. and the mixture was agitated for 30 minutesat ambient temperature and 15 minutes at 60 C. After the addition of 30cc of water, the mixture stood for 2 hours and was then extracted withchloroform. After washing the extracts with water and evaporating offthe chloroform, crystals were obtained which when recrystallized from 50percent ethanol give a 70 percent yield of2-acetoxy-3-methoxy-5-allyl-N-(B-hydroxyethy1)-benzamide in the form ofcolorless crystals and melting at 94 C. (Yield 70 percent).

Analysis: C H NOQ; molecular weight 335.24 Calculated: N% 4.17 Found:4.12

As far asis known, this compound is not described in the literature.

EXAMPLE XIV Preparation of 2-hydroxy-3-methoxy-5-ally1-N- Ipyrrolidine-benzamide Step A:2-hydroxy-3-methoxy-N-pyrrolidino-benzamide A mixture of g. of the ethylester of 2-hydroxy-3-methoxy-benzoic acid and 60 g. of pyrrolidine wereheated at reflux for 3 hours and then the excess pyrrolidine wasdistilled off in vacuo. The residue was dissolved in chloroform whichwas washed with dilute hydrochloric acid and evaporated to dryness invacuo and the residue after crystallization from ethyl acetate gave 19.7g. (70 percent yield) of colorless crystals melting at 124 C. which was2-hydroxyB-methoxy-N-pyrrolidino-benzamide.

Analysis: C I-1,910 molecular weight 221.26 Calculated: N% 6.33 Found:6.25

As far as is known, this compound is not described in the literature.

Step B: 2-hydroxy-3-methoxy-5-ally1N-pyrrolidinobenzamide A mixture of17.20 g of 2-hydroxy-3-methoxy-N-pyrrolidino-benzamide, 11.0 g of allylbromide and 11.1 g of potassium carbonate in 18 cc of acetone was heatedat reflux for 8 hours and after the addition of 75 cc of water, themixture was extracted with chloroform. The organic phases were washedwith N-sodium hydroxide and distilled in vacuo. The crude2-allyloxy-3-methoxy-N-pyrrolidino-benzamide thus obtained was heatedgradually to 200 C. and held at reflux for minutes. After cooling,dilute sodium hydroxide was added thereto and the mixture was extractedwith chloroform. The alkaline phase was acidified with dilutehydrochloric acid and extracted with chloroform. After evaporating offthe chloroform, the residue was crystallized from acetone to obtain a 25percent yield of colorless crystals, melting at 154 C. The product wasidentical with that obtained in Example VlI.

As far as is known, 2-allyloxy-3-methoxy-N-pyrrolidinobenzamide is notdescribed in the literature.

' EXAMPLE XV Preparation of 2-hydroxy-3-methoxy-5-allyl-benzamide StepA: Ethyl ester of 2-benzy1oxy-3-methoxy-benzoic acid 14 g. of ethylester of 2-hydroxy-3-methoxy-benzoic acid were introduced into asolution of 1.62 g of sodium in 100 cc of absolute alcohol and afterfiltering off the sodium phenolate thus formed, the product was driedand dissolved in 310 cc of dimethylformamide. 9.88 g of benzyl chloridewere added to the solution thus obtained and then heated at 120 C. for 2hours. After cooling, the mixture was filtered and evaporated off todryness. The residue was dissolved in ether and the etheral solution waswashed with dilute sodium hydroxide, then with water and evaporated todryness to obtain a 75.5 percent yield of the ethyl ester of2-benzyloxy-3-methoxybenzoic acid in the form of an oil which distilledat 176-180 C. under 0.4 mm. I Analysis: C I-1, 0 molecular weight 286.31Molecular weight found: 288.2

Step B: 2-benzyloxy-3-methoxy-benzoic acid The ethyl ester of2-benzyloxy-3-methoxybenzoic acid obtained in Step A was saponified byrefluxing for 30 minutes in alcoholic potassium hydroxide. Aftercooling, a 62 percent yield of crystals of 2-benzyloxy-3-methoxy-benzoicacid was obtained which were recrystallized from isopropyl ether. Thecolorless crystals thus formed melt at 90 C. Analysis: C l-1 .0molecular weight 258.26 Molecular weight found: 257.5

Step C: 2-benzyloxy-3-methoxy-benzamide 7 g of2-benzyloxy-3-methoxy-benzoic acid were reacted with 3.55 g of thionylchloride dissolved in 70 cc of chloroform by heating at reflux for 2hours and then distilling off the solvent under reduced pressure. Thecrude acid chloride was introduced into 50 cc of concentrated ammoniaand crystals thus formed werefiltered off and recrystallized from etherto obtain a 32 percent yield of colorless crystals of2-benzyloxy-B-methoxy-benzamide melting at 70 C.

Analysis: C I-1 F10 molecular weight 25 7.27 Calculated: N% 5.44 Found:5.57

Step D: 2-hydroxy-3-methoxy-benzamide 2.57 g of2-benzyloxy-3-methoxy-benzamide dissolved in 50 cc of absolute alcoholwere hydrogenated for a few minutes in the presence of 0.5 g ofpalladinized animal charcoal. After filtering and evaporating off thealcoholic solvent, the product thus obtained was recrystallized fromisopropanol to obtain 2- hydroxy-3-methoxy-benzamide in the form ofcolorless crystals melting at 154 C. (Yield: 70 percent).

Analysis: C l-1 1N10 molecular weight Calculated: N% 8.37 Found: 8.58

As far as is known, this compound is not described in the literature.

Step E: 2-allyloxy-3-methoxy-benzamide 1.71 g of2-hydroxy-3-methoxybenzamide, 1.41 g of potassium carbonate and 1.45 gof allyl bromide were suspended in 12 cc of acetone and the mixture washeated at reflux for 8 hours. Then, the acetone was evaporated off invacuo and the residue was dissolved in water and extracted with ether.The ethereal solution was washed with N sodium hydroxide and with water,then evaporated in vacuo to obtain a 95.5 percent yield of colorlesscrystals of 2-allyloxy-3-methoxy-benzamide, melting at C. The productwas insoluble in water and dilute sodium hydroxide.

Analysis: c H NO molecular weight 207.21 Calculated: N% 6.76 Found: 6.75

As far as is known, this compound is not described in the literature.

Step F: 2-hydroxy-3-methoxy-S-allyl-benzamide l g of2-allyloxy-3-methoxy-benzamide was heated at 200 C. for 20 minutes toobtain a 30 percent yield of 2-hydroxy-3- methoxy-5-allyl-benzamide inthe form of colorless crystals after cooling and recrystallization frombenzene which melts at 142 C.

Analysis: C H NO molecular weight 207.21 Calculated: N% 6.76 Found: 6.80

As far as is known, this compound is not described in the literature.

11 12 PHARMACOLOGICAL STUDY B. Choleretic Activity of z h' iimx-smethoxy-S-allyl-N- morpholino-benzamide on rats: Cholereuc Acuvny onRats 2-hydroxy-3-methoxy-5-allyl-N-morpholino-benzamide administeredunder the same experimental circumstances as in A at a dosage of 50mg/kg provided the results shown in Table V.

The choloretic activity of 2-hydroxy-3-methoxy-5-allyl-N-(B-hydroxyethyl)-benzamide was compared with sodium dehydrocholate undersimilar experimental conditions and TABLE V- 50 MGJKG-N-MORPIIOLINO-BENZAMIDE dosages on rats. Groups of 6 male rats having anaverage body weight of 250 to 300 gm were anesthestized with urethaneand Rate of biliary flow in ml. per 30 min.

their hepatic duct was catheterized. The test compounds in 10 aqueoussuspension were administered introduodenally at doses of and 50 mg/kg.The rate of bile flow was measured of the product and 60 minutes beforethe admimstratlon of the test com- Animals:

F0005 0-4413W1N 0 0 00 0 0 500500 0 4-4352 0 00 0 0 0 000 0 445 3 00 0 00 0 5055 3 1-l5 00 0 0 0 0 050050 447753 pounds and every half hour forthe following three hours. The results are shown in Tables I to IV-ALLYL- N-(fl-HYDROXYETIIYL)-BENZAI\IIDE TABLE I.25 MGJKG.2-HYDROXY-3-METHOXY-5 20 Percentage ofvariatiou.....-. +53 +44 +20 +3Average Rate of bile flow in cc. per 30 minutes Minutes Minutes afteradministration of before product Animals:

Pharm. Fr., Vol. 21, 1963, No. 7-8). To avoid permanent anesthesia whichcauses a decline of intestinal movement, the

rats having an average body weight of 250300 gm were anesthetized forseveral minutes with ether to permit Average.

Percentage of catheterization of the he atic duct. The test roducts in anevariation +07 +51 +27 +18 +12 -3 30 p p q TABLE II.50 MGJKG.2-IIYDROXY-3-METHOXY-5-ALLYL- ous suspension were administered orallywith an esophageal probe at doses of 25 and 50 mg/kg and the bile flowwas measured as in A. Theresults are shown in Tables VI to IX.

N-(B-HYDROXYETIIYIJ-BENZAMIDE v TABLE VI.-25 MGJKG.2-HYDROXY-Zi-METIIOXY-fi-ALLYL- Rate of biliary flow in ml. per 30 min.

N-(B-HYD ROXYETIIYL) -BENZAMII)E Rate of biliary flow in ml. per 30 min.

Minutes Minutes after administration before of the product MinutesMinutes after administration before of the product 40 30 40 Animals: 40

Animals:

Percentage ofvariation +87 +48 Average P rcentage of varia i -ALLYL-TABLE Vii-50 MG./KG. 2-HYDROXY-3-ME'IIIOXY-5 TABLE III.25 MGJKG. SODIUMDEHYDROCHOLATE Rate of biliary flow in ml. per 30 min.

Rate of biliary How in ml. per 30 min.

Minutes Minutes after administration Minutes Minutes afteradministration before of the product before of the product AveragePcrcentageofvariation +38 +18 +10 +8 Animals:

Average 0.40 .72 0.78 0.74 0.66 0.59 0.43

Percentageofvariation... +05 +05 +47 TABLE IV.50 HGJKG. SODIUHDEHYDROCHOLATE TABLE vnr s Malice. DEH'YD'ROCHOLATE OF SODIUM Rate ofbiliary flow in ml. per 30 min.

Minutes before Rate of biliary flow in ml. per 30 min.

Minutes after administration of the product Minutes Minutes afteradministration before of the product Percentageofvariation. +35 +37 +12+12 Animals:

Percentage of vuriatiou Minutes 1 Minutes after administration before ofthe product Average 0. 61 .0. 56 0. 44 0. 44 0. 0. 37

Percentage of variation +74 +60 +26 +26 +14 +6 DETERMINATION OF ACUTETOXICITY Intravenous Way: lntraperitoneal Way:

or. 217 mg/kg DL 209 mg/kg Subcutaneous Way D1. 2g/kg Oral way: DL 3g/kgSYMPTOMATOLOGY At elevated dosages, a depressive action was observed anda hypotension which was accompanied by an acceleration of the cardiacfrequency and the respiratory rhythm occurred.

B. The acute toxicity of 2-hydroxy-3methoxy-5-allyl-N-morpholino-benzamide was determined intraperitoneally and subcutaneouslyunder the same conditions. The following results were obtained:

lntrapcritioneal way: Subcutaneous Way:

1 g/kg 2/g kg Various modifications of the compositions and method ofthe invention may be made without departing from the spirit or scopethereof and it is to be understood that the invention is to be limitedonly as defined in the appended claims.

We claim:

1. An amide of 2-hydroxy-3-methoxy-5-allyl-benzoic acid of the formulaCH O OR 5- R1 is. Br-Q FQH2 wherein R is selected from the groupconsisting of hydrogen, alkyl of one to seven carbon atoms and acyl ofan organic hydrocarbon carboxylic acid of one to 18 carbon atoms, R andR are selected from the group consisting of hydrogen, alkyl andhydroxyalkyl of one to seven carbon atoms, lower alkanoyl oxyalkyl ofone to seven alkyl carbon atoms, phenyl and cyclohexyl.

2. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-(B-hydroxyethyl)-ben2amide.

3. A compound of claim 1 which is 2,3-dimethoxy-5-allyl-N-(,B-hydroxyethyl)-benzamide.

4. A compound of claim 1 which is 2-hydroxy-3-methoxy-5- alll-N-(B-hydroxypro yl)-benz amide.

. A compound of c arm 1 which 18 2-hydroxy-3-methoxy-5-allylbenzanilide.

6. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-cyclohexylbenzamide.

7. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-n-propylbenzamide.

8. A compound of claim 1 which is 2-acetoxy-3-methoxy-5-allylbenzanilide.

9. A compound of claim 1 which is 2-acetoxy-3-methoxy-5-allyl-N-n-propylbenzamide.

10. A compound of claim 1 which is 2 acetoxy-3-methoxy-5-allyl-N-cyclohexylbenzamide.

11. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-diethylbenzamide.

12. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allylbenzamide.

13. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-(a,a-dimethyl-fl-hydroxycthyl)-benzamide.

14. A compound of claim 1 which is 2-acetoxy-3-methoxy-5-allyl-N-(B-acetoxyethyl)-benzamide.

2. A compound of claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-( Beta-hydroxyethyl)-benzamide.
 3. A compound of claim 1 which is2,3-dimethoxy-5-allyl-N-( Beta -hydroxyethyl)-benzamide.
 4. A compoundof claim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-( Beta-hydroxypropyl)-benzamide.
 5. A compound of claim 1 which is2-hydroxy-3-methoxy-5-allylbenzanilide.
 6. A compound of claim 1 whichis 2-hydroxy-3-methoxy-5-allyl-N-cyclohexylbenzamide.
 7. A compound ofclaim 1 which is 2-hydroxy-3-methoxy-5-allyl-N-n-propylbenzamide.
 8. Acompound of claim 1 which is 2-acetoxy-3-methoxy-5-allylbenzanilide. 9.A compound of claim 1 which is2-acetoxy-3-methoxy-5-allyl-N-n-propylbenzamide.
 10. A compound of claim1 which is 2-acetoxy-3-methoxy-5-allyl-N-cyclohexylbenzamide.
 11. Acompound of claim 1 which is2-hydroxy-3-methoxy-5-allyl-N-diethylbenzamide.
 12. A compound of claim1 which is 2-hydroxy-3-methoxy-5-allylbenzamide.
 13. A compound of claim1 which is 2-hydroxy-3-methoxy-5-allyl-N-( Alpha , Alpha -dimethyl- Beta-hydroxyethyl)-benzamide.
 14. A compound of claim 1 which is2-acetoxy-3-methoxy-5-allyl-N-( Beta -acetoxyethyl)-benzamide.